US11512065B2ActiveUtilityPatentIndex 83
GPR119 agonists
Est. expiryOct 7, 2039(~13.3 yrs left)· nominal 20-yr term from priority
C07D 401/14C07D 401/04A61P 3/00A61K 45/06A61K 31/506C07D 405/14C07H 15/26C07D 403/14C07D 401/12
83
PatentIndex Score
7
Cited by
244
References
20
Claims
Abstract
This disclosure is directed, at least in part, to GPR119 agonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR119 agonists are gut-restricted compounds. In some embodiments, the condition or disorder is a metabolic disorder, such as diabetes, obesity, nonalcoholic steatohepatitis (NASH), or a nutritional disorder such as short bowel syndrome.
Claims
exact text as granted — not AI-modifiedWe claim:
1. A compound of Formula (IIa):
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R 1 is hydrogen, —OH, or C 1-8 alkyl, wherein the alkyl is unsubstituted or substituted by —OH or —O(C 1-6 alkyl);
each R 2 and R 3 is hydrogen;
or R 2 and R 3 on the same carbon atom are taken together to form ═O;
R 4 is hydrogen or C 1-6 alkyl;
R 5 is C 1-8 alkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocycloalkyl, —[(CH 2 ) r —Z] t —R 6 , —[(CHR d ) r —Z] t —R 6 , or —[(C(R d ) 2 ) r —Z] t —R 6 ; wherein each alkyl, cycloalkyl, and 4- to 8-membered heterocycloalkyl is substituted by 1-6 R c groups
each Z is independently —CH 2 O—, —CH 2 NR d —, —CH 2 N + (R d ) 2 —, or —NH—C(═O)—NH—;
each r is independently 1-6;
each t is independently 1-6;
R 6 is hydrogen, C 1-8 alkyl, C 3-8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, or 4- to 8-membered heterocycloalkyl is unsubstituted or substituted by 1-6 R c groups;
or R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 4- to 8-membered heterocycloalkyl, which is unsubstituted or substituted by 1-6 R c groups;
each R c is independently —OH, —CH 2 OH, —NH 2 , —N(R d ) 3 + , —C(═O)OH, —S(═O) 2 OH, —S(═O) 2 NH 2 , —P(═O)(OH) 2 , —P(═O)(OH)(R d ), —P(═O)(OH)(OR d ),
each R d is independently C 1-6 alkyl;
each R a is independently halogen, —CN, C 1-6 alkyl, C 1-6 fluoroalkyl, or C 3-6 cycloalkyl;
W is phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents selected from R b ;
each R b is independently halogen, —OH, —CN, —C(O)OH, —C(O)O(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, alkoxy, and cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy;
or W is —C(═O)O—R 22 ;
R 22 is C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted by 1-3 substituents independently selected from fluorine, —OH, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
n is 0-4;
p is 1 or 2;
q is 1 or 2; and
s is 1 or 2.
2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is phenyl or 5- or 6-membered monocyclic heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents selected from R b .
3. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is phenyl or 6-membered monocyclic heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from R b ; and
each R b is independently halogen, —C(O)OH, —C(O)O(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl; wherein each alkyl, alkoxy, and cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy.
4. The compound of claim 2 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is 6-membered monocyclic heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from R b ; and
each R b is independently —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OH, or —C(O)OCH 3 .
5. The compound of claim 1 , wherein the compound has the structure of Formula (IIb):
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is —C(═O)O—R 22 ; and
R 22 is C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, cycloalkyl, or heterocycloalkyl is unsubstituted or substituted by 1-3 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
p is 1; and
q is 1.
8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 4 is hydrogen or C 1-4 alkyl;
R 5 is C 1-8 alkyl, —[(CH 2 ) r —Z] t —R 6 , —[(CHR d ) r —Z] t —R 6 , or —[(C(R d ) 2 ) r —Z] t —R 6 ;
wherein the alkyl is substituted by 1-6 R c groups;
each Z is independently —CH 2 O—, —CH 2 NR d —, or —NH—C(═O)—NH—;
r is 1-3;
t is 1-3; and
R 6 is hydrogen or C 1-8 alkyl, wherein the alkyl is substituted by 1-6 R c groups.
9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
each R c is independently —OH, —CH 2 OH, —NH 2 , —N(R d ) 3 + , —C(═O)OH, or
10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 5 is C 1-8 alkyl which is substituted by 1-6 R c groups; and
each R c is independently —OH, —CH 2 OH, —N(R d ) 3 + , —C(═O)OH, or
11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
R 4 and R 5 are taken together with the nitrogen to which they are attached to form a 5- or 6-membered heterocycloalkyl, which is unsubstituted or substituted by 1-3 —OH groups.
12. The compound of claim 1 , wherein the compound has the structure of Formula (IIc) or (IId):
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
13. The compound of claim 12 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is phenyl or 6-membered monocyclic heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from R b ;
each R b is independently halogen, —C(O)OH, —C(O)O(C 1-6 alkyl), C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl; wherein each alkyl, alkoxy, and cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, —OH, C 1-6 alkyl, and C 1-6 alkoxy;
R 4 is hydrogen or C 1-4 alkyl;
R 5 is C 1-8 alkyl, —[(CH 2 ) r —Z] t —R 6 , —[(CHR d ) r —Z] t —R 6 , or —[(C(R d ) 2 ) r —Z] t —R 6 ;
wherein the alkyl is substituted by 1-6 R c groups;
each Z is independently —CH 2 O—, —CH 2 NR d —, or —NH—C(═O)—NH—;
r is 1-3;
t is 1-3; and
R 6 is hydrogen or C 1-8 alkyl, wherein the alkyl is substituted by 1-6 R c groups.
14. The compound of claim 12 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:
W is 6-membered monocyclic heteroaryl, wherein the heteroaryl is unsubstituted or substituted with 1 or 2 substituents selected from R b ;
each R b is independently —F, —Cl, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 OH, —CH 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)OH, or —C(O)OCH 3 ;
R 4 is hydrogen or C 1-4 alkyl;
R 5 is C 1-8 alkyl which is substituted by 1-6 R c groups; and
each R c is independently —OH, —CH 2 OH, —N(R d ) 3 + , —C(═O)OH, or
15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]acetyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]azetidine-3-carboxamide;
1-[2-[2-fluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]acetyl]-N-[2-[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]carbamoylamino]ethyl]azetidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]azetidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]azetidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2,3-dihydroxy-2-(hydroxymethyl)propyl]azetidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2-[rac-(2S,3S,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydropyran-2-yl]oxyethyl]azetidine-3-carboxamide;
2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]acetamide;
2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]-N-[2,3-dihydroxy-2-(hydroxymethyl)propyl]acetamide;
2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]acetyl]azetidin-3-yl]-N-[2,3-dihydroxy-2-(hydroxymethyl)propyl]acetamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]azetidine-3-carboxamide;
2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]-N-[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]acetamide;
1-[2-[2-fluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]acetyl]-N-[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]azetidine-3-carboxamide;
3-[[1-[2-[2,6-difluoro-4-[3-[1-(5-propylpyrimidin-2-yl)-4-piperidyl]propoxy]phenyl]acetyl]azetidine-3-carbonyl]amino]propyl-trimethyl-ammonium formate;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2,3-dihydroxy-2-(hydroxymethyl)propyl]piperidine-4-carboxamide;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[3-hydroxy-2-(hydroxymethyl)propyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[rac-(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[rac-(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[rac-(3S,4R)-3,4-dihydroxypyrrolidin-1-yl]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[rac-(1R,2S,3R,4S)-2,3,4-trihydroxycyclopentyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[rac-(3R,5S)-3,4,5-trihydroxy-1-piperidyl]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[2-[2-(2-hydroxyethoxy)ethoxy]ethylamino]methyl]azetidin-1-yl]ethanone;
1-[3-[[2-[2-(2-aminoethoxy)ethoxy]ethylamino]methyl]azetidin-1-yl]-2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
2-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-1-(3-(2-((1,3-dihydroxypropan-2-yl)amino)ethyl)azetidin-1-yl)ethan-1-one;
2-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-1-(3-(2-((3-hydroxy-2-(hydroxymethyl)propyl)amino)ethyl)azetidin-1-yl)ethan-1-one;
2-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-1-(3-(2-((2,3-dihydroxy-2-(hydroxymethyl)propyl)amino)ethyl)azetidin-1-yl)ethan-1-one;
2-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-1-(3-(2-((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)ethyl)azetidin-1-yl)ethan-1-one;
1-(2-((2-(1-(2-(4-(3-(1-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)acetyl)azetidin-3-yl)ethyl)amino)ethyl)-3-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)urea;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[2-[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]ethyl]azetidin-1-yl]ethanone;
2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-1-(3-(((3-hydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)ethan-1-one;
1-(3-(((2,3-dihydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)ethan-1-one;
1-(3-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)azetidin-1-yl)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)ethan-1-one;
1-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-3-(2-(((1-(2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)acetyl)azetidin-3-yl)methyl)amino)ethyl)urea;
(2S,3R,4S,5S)-6-[[1-[2-[4-[3-[1-(5-ethylpyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]methylamino]-2,3,4,5-tetrahydroxy-hexanoic acid;
1-(3-(((2,3-dihydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)-2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)ethan-1-one;
1-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-3-(2-(((1-(2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)acetyl)azetidin-3-yl)methyl)amino)ethyl)urea;
2-(4-(3-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-2,6-difluorophenyl)-1-(3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-1-yl)ethan-1-one;
2-(2-fluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1-(3-(((3-hydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)ethan-1-one;
1-(3-(((2,3-dihydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)-2-(2-fluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)ethan-1-one;
1-(3-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)azetidin-1-yl)-2-(2-fluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)ethan-1-one;
1-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-3-(2-(((1-(2-(2-fluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)acetyl)azetidin-3-yl)methyl)amino)ethyl)urea;
2-(2-fluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1-(3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-1-yl)ethan-1-one;
2-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1-(3-(((2,3-dihydroxy-2-(hydroxymethyl)propyl)amino)methyl)azetidin-1-yl)ethan-1-one;
2-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1-(3-(((1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)azetidin-1-yl)ethan-1-one;
1-(2-(((1-(2-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)acetyl)azetidin-3-yl)methyl)amino)ethyl)-3-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)urea;
2-(2,6-difluoro-4-(3-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)propoxy)phenyl)-1-(3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-1-yl)ethan-1-one;
2-[2-fluoro-4-[3-[1-(5-methoxypyrimidin-2-yl)-4-piperidyl]propoxy]phenyl]-1-[3-[[[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
1-[2-[[1-[2-[2-fluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]acetyl]azetidin-3-yl]methylamino]ethyl]-3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]urea;
(3R,5R)-7-[[1-[2-[2-fluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]acetyl]azetidin-3-yl]methylamino]-3,5-dihydroxy-heptanoic acid;
2-[2-fluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
methyl 2-[4-[3-[3-fluoro-4-[2-oxo-2-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethyl]phenoxy]propyl]-1-piperidyl]pyrimidine-5-carboxylate;
2-[2-fluoro-4-[3-[1-[5-(hydroxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3R)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3R)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
(3R)-1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]pyrrolidine-3-carboxamide;
(3S)-1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]pyrrolidine-3-carboxamide;
N-[2,3-dihydroxy-2-(hydroxymethyl)propyl]-2-[1-[2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]acetamide;
isopropyl 4-[3-[3-fluoro-4-[2-oxo-2-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethyl]phenoxy]propyl]piperidine-1-carboxylate;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethanone;
(1-methylcyclopropyl) 4-[3-[3-fluoro-4-[2-oxo-2-[3-[[[rac-(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethyl]phenoxy]propyl]piperidine-1-carboxylate;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-(methoxymethyl)-3-[[[r(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]-3-(methoxymethyl)pyrrolidin-1-yl]ethanone;
[3-(trifluoromethyl)oxetan-3-yl] 4-[3-[3-fluoro-4-[2-oxo-2-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethyl]phenoxy]propyl]piperidine-1-carboxylate;
[3-(trifluoromethyl)oxetan-3-yl] 4-[3-[3,5-difluoro-4-[2-oxo-2-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]azetidin-1-yl]ethyl]phenoxy]propyl]piperidine-1-carboxylate;
(3S)-1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
(3S)-1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]acetyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
(3S)-1-[2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
(3S)-1-[2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]acetyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
(3S)-1-[2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]acetyl]-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[(3S)-3-[[[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]amino]methyl]pyrrolidin-1-yl]ethanone;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-3-(methoxymethyl)-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-N-[3-hydroxy-2,2-bis(hydroxymethyl)propyl]-3-(methoxymethyl)pyrrolidine-3-carboxamide;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3S)-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[(3S)-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[(3S)-3-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[(3S)-3-[[[2,3-dihydroxy-2-(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[(3S)-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[2-[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]ethyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[(2S,3R,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-[[[(2R,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[(3R)-3-[[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidine-3-carbonyl]amino]ethanesulfonic acid;
3-[[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidine-3-carbonyl]amino]propane-1-sulfonic acid;
4-[[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidine-3-carbonyl]amino]butane-1-sulfonic acid;
5-[[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidine-3-carbonyl]amino]pentane-1-sulfonic acid;
6-[[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidine-3-carbonyl]amino]hexane-1-sulfonic acid;
2-[[2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]acetyl]amino]ethanesulfonic acid;
3-[[2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]acetyl]amino]propane-1-sulfonic acid;
4-[[2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]azetidin-3-yl]acetyl]amino]butane-1-sulfonic acid;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-hydroxy-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-3-hydroxy-N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl]pyrrolidine-3-carboxamide;
1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-3-hydroxy-N-[3-hydroxy-2,2-bis(hydroxymethyl)propyl]pyrrolidine-3-carboxamide;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[4-hydroxy-4-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]-1-piperidyl]ethanone;
2-[1-[2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]acetyl]-3-hydroxy-azetidin-3-yl]-N-[3-hydroxy-2,2-bis(hydroxymethyl)propyl]acetamide;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-hydroxy-3-[[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]azetidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[3-hydroxy-3-[[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2-fluoro-phenyl]-1-[4-hydroxy-4-[[[(2S,3S,4R)-2,3,4,5-tetrahydroxypentyl]amino]methyl]-1-piperidyl]ethanone;
2-[4-[3-[1-(5-chloropyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[3-hydroxy-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
2-[4-[3-[1-(5-ethoxypyrimidin-2-yl)-4-piperidyl]propoxy]-2,6-difluoro-phenyl]-1-[3-hydroxy-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone; and
2-[2,6-difluoro-4-[3-[1-[5-(methoxymethyl)pyrimidin-2-yl]-4-piperidyl]propoxy]phenyl]-1-[3-hydroxy-3-[[[3-hydroxy-2,2-bis(hydroxymethyl)propyl]amino]methyl]pyrrolidin-1-yl]ethanone;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
16. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.
17. A method of treating a condition or disorder involving the gut-brain axis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the condition or disorder is associated with GPR119 activity.
18. The method of claim 17 , wherein the condition or disorder is a metabolic disorder or a nutritional disorder.
19. The method of claim 17 , wherein the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, hypertension, short bowel syndrome, intestinal failure, intestinal insufficiency, chemotherapy-induced enteritis or radiation-induced enteritis.
20. The method of claim 17 , further comprising administering one or more additional therapeutic agents to the subject; wherein the one or more additional therapeutic agents are selected from a TGR5 agonist, a GPR40 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor, a GLP-1 receptor agonist, metformin, or a combination thereof.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.